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Molecular targeted therapy in enteropancreatic neuroendocrine tumors: from biology to clinical practice
1Unit of Gastrointestinal and Neuroendocrine Tumor, European Institute of Oncology, Via Ripamonti 435 20141 Milan, Italy. nicola.fazio@ieo.it.
Abstract:
Advanced enteropancreatic (EP) neuroendocrine tumors (NETs) can be treated with several different therapies, including chemotherapy, biotherapy, and locoregional treatments. Over the last few decades, impressive progress has been made in the biotherapy field. Three main druggable molecular targets have been studied and developed in terms of therapy: somatostatin receptor (sstr), mammalian target of rapamycin (mTOR), and angiogenic factors. In particular, research has moved from the old somatostatin analogs (SSAs), such as octreotide (OCT) and lanreotide (LAN), specifically binding to the sstr-2, to the newer pasireotide (PAS), which presents a wider sstr spectrum. Over the last ten years, several molecular targeted agents (MTAs) have been studied in phase II trials, and very few of them have reached phase III. The mTOR inhibitor everolimus and the multitargeted inhibitor sunitinib have been approved for clinical use by the FDA and EMA in advanced well/moderately-differentiated (WD, MD) progressive pancreatic neuroendocrine tumors (PNETs), on the basis of the positive results of two international large randomized phase III trials vs. placebo. Bevacizumab has been studied in a large US phase III trial vs. interferon (IFN)-alfa2b, and results are pending. In this review, the biological and clinical aspects of MTAs introduced into clinical practice or which are currently in an advanced phase of clinical investigation are addressed.
Insights
Advanced neuroendocrine tumors (NETs) show progress in biotherapy targeting somatostatin receptors, mTOR, and angiogenic factors. Molecular targeted agents like everolimus and sunitinib are approved for pancreatic NETs, with others in advanced trials.
Area of Science:
- Oncology
- Endocrinology
- Pharmacology
Background:
- Advanced enteropancreatic neuroendocrine tumors (EP NETs) treatment landscape includes chemotherapy, biotherapy, and locoregional therapies.
- Biotherapy has advanced significantly, focusing on three key molecular targets: somatostatin receptors (sstr), mammalian target of rapamycin (mTOR), and angiogenic factors.
- Therapeutic strategies have evolved from older somatostatin analogs (SSAs) like octreotide and lanreotide to newer agents such as pasireotide with a broader sstr spectrum.
Purpose of the Study:
- To review the biological and clinical aspects of molecular targeted agents (MTAs) in advanced EP NETs.
- To discuss MTAs that have been approved for clinical use or are in advanced clinical investigation.
- To highlight the progress in biotherapy for EP NETs.
Main Methods:
- Review of clinical trial data for MTAs in advanced EP NETs.
- Analysis of approved therapies including everolimus and sunitinib for pancreatic NETs (PNETs).
- Inclusion of ongoing trials, such as bevacizumab for PNETs.
Main Results:
- Everolimus and sunitinib are approved for advanced well/moderately-differentiated progressive PNETs based on positive phase III trials.
- Several MTAs have been investigated in phase II trials, with limited progression to phase III.
- Results for bevacizumab in a large phase III trial are pending.
Conclusions:
- Molecular targeted agents represent a significant advancement in the treatment of advanced EP NETs.
- Approved therapies like everolimus and sunitinib have demonstrated efficacy in specific PNET populations.
- Ongoing research and clinical trials continue to expand therapeutic options for EP NETs.
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